Derivatives of 1-aminopropane



United States Patent i 2,991,289 DERIVATIVES 0F l-AMINOPROPANE Karl Schulte, Darmstadt, Germany, assignor to E. Merck ktrengesellschaft,Darmstadt, Germany, a corporat1on of Germany No Drawing. Filed Feb. 2,1959, Ser. No. 790,340 Claims priority, application Germany Feb. 5, 19587 Claims. (Cl. 260-296) During investigations seeking to discover ahighly efficient analgesic compound, it has been found as a result ofvery comprehensive research work that derivatives of l-aminopropanehaving the general formula:

wherein X designates halogen, alkyl and alkoxy; R and R designatestraight chained or branched alkyl radicals which together have from 1to 6 carbon atoms, and whereof R, can also be hydrogen, and wherein theunit N-rilin also stands for piperidino, pyrrolidino and morpholino,possess excellent analgesic characteristics. of the above formula havenot been described heretofore in the literature, but some compoundsstructurally similar thereto are used as antihistamines.

The present invention relates to analgesic-acting derivatives ofl-anfinopropane of the general Formula I, and the method of preparingthem, and includes the pharmaceutically acceptable salts thereof formedfrom inorganic and organic acids, as for example, hydrochloric,sulfuric, phosphoric, maleic, tartaric, citric, benzoic, salicylic,i.e., acids normally employedto form salts with therapeutically activeamines.

It has been further found that derivatives of l-aminopropane of theabove Formula I, wherein X designates a para-chloro or para-bromosubstituent, and R and R are straight chained or branched alkyl radicalswhich together have from 1 to 4 carbon atoms and whereof R can also behydrogen, show particularly marked analgesic activity and low order oftoxicity.

According to the invention, the compounds of Formula I are obtained when(a) Benzylpyridine derivatives of the general formula RH wherein R is abivalent radical of the formula:

(Formula II) wherein X has the significance defined in Formula I, arereacted with an aminoethyl halogenide of the general formula Compoundswherein Y is halogen, preferably chlorine or bromine,

and R and R and the unit NR,1-R1 V have the above stated significance toform compounds of the general Formula I.

The compounds according to the invention can also be synthesized:

(b) From compounds with the basic structure of the general Formula I,which contain non-aromatic C;C and/or double bonds, by converting suchdouble bond or bonds into saturated bonds by applying conventionalmethods, or

(c) From compounds of the general structure of general Formula I, whichcontain a radical at carbon 3 of the propyl group that can be replacedby hydrogen, as for instance, a chlorine, bromine or iodine atom, or aNEC-, HOOC--, H- NCO or alkyl N-CO- alkyl group by replacing suchradical with hydrogen by methods known as such.

The preparation of compounds according to the gen eral Formula I alsoproceeds by (d) Catalytic hydrogenation of the compounds of the generalformula Rl-ICH CN, Where R has the above stated significance, in thepresence of a monoor dialkylamine, whereof the alkyl radicals have atotal of 1 to 6 carbon atoms, or the dialkyl-amine contains the unitNR{R,

as defined above.

(e) By condensation of an acetal of the general formula:

O-alkyl RH-CHz-CH O-alkyl wherein R has the above stated significancewith a dialky formamide of the general formula:

I HN/ N-Rnt,

have the above stated significance, andX' stands for a halogen.

Finally, the compounds according to the invention can be obtained- (g)From compounds of the Formula I which contain hydrogen instead of R and/or R by replacing such hydrogen atoms with substituents R and/or R bymethods known as such, or-

Patented July 4, 1961 '1 (J (h) From compounds of the general formula:

RHCH CH NSO1Ar wherein R has the above stated significance, Ar is anaromatic hydrocarbon radical, and R is an alkyl radical having 1 to 4carbon atoms, by replacing the SO -Ar group with hydrogen by treatmentwith saponifying agents.

More specifically, it is advantageous to observe the following when theabove described methods, (a) to (h), are carried out.

(a) The alkylation reaction is preferably carried out by firstmetallizing one of the two active hydrogen atoms of the benzylpyridinecompound by methods known as such. Such a metallization can be obtained,for example, by treatment of the benzylpyridine compound with sodiumamide in liquid ammonia and in the presence of a suitable hydrocarbon,such as, toluene or xylene. One can also introduce an alkali metal atomby reaction with alkali metal organic compounds, as for example, lithiummethyl or sodium phenyl.

(b) The hydrogenation of the C=C- double bond is preferably carried outcatalytically in the presence of a precious metal catalyst, as forexample, palladium. The Schiff bases are suitably hydrogenated by nickelcatalysts. It is advantageous to operate at a slightly elevatedpressure.

The substitution of the aliphatically bound halogen atom (chlorine,bromine or iodine) can be efiected by hydrogenation in the presence of aprecious metal catalyst. To efiect saponification and/or decarboxylationof the NE( r-, HOOC--, H N-CO- or Alkyl N-CO Alkyl group, the compoundmay be boiled with 70 percent sulfuric acid or with butanolic alkalimetal hydroxide, e.g., potassium or sodium hydroxide. The saponificationor decarboxylation can also be effected by treatment with sodium amidein xylene or by reaction with a metallic organic compound (Grignardcompound or alkali metal alkyl) in an inert saponification medium, suchas anisole, toluene or xylene, at a temperature of about 70 C.

(d) The catalytic hydrogenation of the nitrile of the formula RH-CH CN(R has the same significance as stated above) is preferably carried outin the presence of a nickel or cobalt catalyst.

(e) The reaction of the acetal with a dialkyl formamide occursparticularly favorably in the presence of hydrogen chloride and formicacid.

(g) The alkylation at the nitrogen can be effected under the usualconditions. The reaction with formaldehyde in the presence of formicacid is particularly suitable for the introduction of methyl groups.Depending upon the reaction conditions employed, either the monoor thedimethylamino compound is obtained.

The compounds according to the invention are highly efl'icient analgesiccompounds. The eificiency seems to be limited to the small group ofcompounds according to the invention, since even slight changes in themolecular structure, for instance, the introduction of other alkylgroups into the pyridine ring, or the substitution at the nitrogen byother than the stated alkyl radicals, result in the marked decrease ofthe efficiency.

The analgesic action is particularly marked for 1-(6-isobutylpyridyl-Z)-1-(p-bromophenyl) 3 diethylaminopropane andl-(6-isobutyl-pyridyl-2)-l-(p-bromophenyl)-3-dimethylamino-propane.These two compounds have a pronouncedly stronger analgesic action than4- dimethylamino-l,S-dirnethyl-Z-phenyl 3 pyrazolone (A) orl,2-diphenyl-3,5-dioxo 4 n butylpyrazolidine (B). Comparative tests withcommercial combination preparations made from (A) and (B) have alsoshownthatthc compounds according to the invention produce a markedlystronger analgesic action; especially, the duration of the analgesicaction is longer with the compounds according to the invention. Forinstance, 5 mg. of l-(6'- isobutylpyridyl-2')-1-(p bromophenyl) 3dirnethylamino-propane per kg. body weight per os is required in orderto obtain the Dosis analgetica 50 after 1 hour. In order to obtain thesame analgesic activity, 20 mg. ofl,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine is required.

In order to obtain analgesic action (Dos. analg. 50) for 20 minutes,only 3.4 mg. of 1-(6'-isobutylpyridyl-2)-l-(p-bromophenyl)-3-diethylarnino-propane per kilo of body weight,orally administered, is required, whereas 400 mg. of a combinationpreparation consisting of1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine-sodium (50%) and 1,5-dimethyl-4-dimethylamine-2-phenyl-3-pyrazolone (50%) is required.

Hence, the compounds according to the invention in comparison with theheretofore known analgesic compounds, show a very striking superiorityin their analgesic action. The tolerance of the new substances is goodand thus the use thereof as a chemotherapeutic agent appears to bejustified.

The following are examples in accordance with this invention. The termTorr as used therein is the international unit of pressure, to wit, apressure of 1 mm. of mercury, atmosphere.

Example 1 4.20 g. (grams) ofa-(B-diethylaminoethyD-a-(6-isobutylpyridyl-Z)-p-bromobenzyl-cyanide in210 g. of 70 percent sulfuric acid was boiled under reflux for 6 hours.The solution was poured on ice, filtered over charcoal, alkalinized withcaustic soda solution (20% concentration), and extracted with diethylether. After drying and concentration by evaporation of the etherealsolution, a residue of 36.5 g. was obtained. Upon distillation, thereofat a pressure of 0.01 Torr, at a temperature of 158-- 162 0, there Wasobtained 31.4 g. of the distillate which wasl-(p-bromophenyl)-1-(6-isobuty1pyridyl-2') 3 diethylamino-propane.

Example 2 To a boiling mixture of 8.4 g. of potassium hydroxide in ccm.of nbutanol, there was added 20 g. of a-(6-isobutylpyridyl-Z)-ot-(fi-dimethylaminoethyl) p bromobenzylcyanideadmixed with a small amount of n-butanol. The mass was boiled for 4hours under reflux. The butanol was removed by vacuum distillation; andthe residue taken up in diethyl ether and water. The ethereal solutionwas shaken up as frequently as necessary with water until it ceased toshow alkalinity to phenophthalein. After drying and concentration byevaporation of the ethereal solution, a residue of 18 .8 g. wasobtained. From this residue there was separated by distillation the1-(6'- isobutylpyridyl-2)-l-(p bromophenyl) 3 dimethylamino-propanehaving a boiling point of 137-140" C. at 0.01 Torr.

Example 3 To a mixture of 3.0 g. of magnesium shavings and 100 ccm. ofanisole there Was added, at 40 C., 13.6 g. of ethylbromide. The massstirred until all of the magnesium went into solution. There was addedto the solution at a temperature of 50-60" C. a mixture of 40 g. ofa-(6-isobutylpyridyl-2)-a-(B-dimethylaminoethyD- p-brornobenzylcyanideand 50 g. of anisole. The mass was stirred at 70 C. for an additional 2hours. After decomposition with ice, the mixture was acidified withhydrochloric acid, shaken up and separated. The anisole was exhausted byshaking up with hydrochloric acid. The acid solution was reacted withammonia; the precipitated base then taken up in diethyl ether andbenzene; and the solvent dried and concentrated by evaporation. Upondistillation of the residue, there was obtained the 1(6'-isobutylpyridyl-2)-1-(p-bromophenyl)-3-dimethylamino-propane, havinga boiling point of 137-140 C. at 0.01 Torr.

Example 4 A mixture of 100 ccm. of liquid ammonia, a small quantity offerric nitrate and 2.3 g. of sodium was stirred for 2 hours. 100 ccm. ofxylene was added thereto and the ammonia evaporated off. After theaddition of 20 g. of a-(6-isobutylpyridyl-2)-u-(,B'-dimethylaminoethyl)-p-bromobenzylcyanide, the mass was boiled under reflux for 24 hours. Themass was decomposed with ice, diluted with diethyl ether and shaken upwith water. Upon distillation of the solvent residue, there was obtainedthe 1-(6'-isobutylpyridyl-2)-1-(p-bromophenyl)-B-dimethylarnino-propane, having a boiling point of 137- 140 C. at 0.01Torr.

Example 5 4.9 g. of crudeu-(6-isobutylpyridyl-2)-a-(p-dimethylaminoethyl) p bromophenylaceticacid dimethylamide [obtained by the condensation ofa-(6-isobutylpyridyl-2)- p-bromophenylacetic acid-dimethylamide and,B-(dimethylamino.) -ethylchloride] was boiled for 5 hours under refluxtogether with 25 g. of 75' percent sulfuric acid. The solution waspoured on ice, extracted with diethyl ether, reacted with an excess ofcaustic soda solution and again extracted with ether. On distillationthe ethereal solution yielded the1-(6-isobutylpyridyl-2')-1-(p-bromophenyl)- 3-dimethylaminopropane,having a boiling point of 137- 140 C. at 0.01 Torr.

Example 6 To 150 ccm. of liquid ammonia, there was added with stirringduring the course of 20 minutes, 6.5 g. of B-methylaminoethylchloride-hydrochloride. Then 50 ccm. of toluene wasadded thereto and the mixture stirred until the ammonia evaporated oif.The precipitated salt was removed by suction filtration and washed withtoluene. The filtrate was employed in accordance with the followingreaction: 200 ccm. of liquid ammonia and a small amount of ferricnitrate were reacted with 1.3 g. of sodium. After stirring for 2 hours,the above described solution of the fi-methylaminoethylchloride intoluene was added to a solution of 15.2 g. of 6-isobutyl-2-p-bromobenzylpyridine in a small quantity of toluene; and after 2 hours100 ccm. oftoluene was added thereto. The mass was stirred overnight atroom temperature. The mixture was decomposed with water and separated.The residue in the toluene, 16.4 g., yielded on distillation the 1-(p-brornophenyl) -1- (6'-isobutylpyridyl-2 -3-methylamino-propane,having a boiling point of 160-161 C. at 0.05 Torr. The dipicrate thereofhas a melting point of 140-142 C. The l-(p-bromophenyl)-1(6-isobuty1-pyridyl-2)-3-ethylaminopropane, obtained by the same method, has aboiling point of 167170 C. at 0.05 Torr. The dipicrate thereof has amelting point of 167-170" C.

Example 7 8.6 g. of ,8-diethylaminoethylchloride-hydrochloride areintroduced while stirring into 200 ccm. of liquid ammonia. 50 ccm. oftoluene are added thereto and the stirring continued until the ammoniais evaporated off. The filtrate obtained from the suction filtration ofthe precipitated salt was employed according to the following treatment:To 200 ccm. of liquid ammonia there was added while stirring 0.1 g. ofiron (III)-nitrate and 3.0 g. of sodium. After 2 hours, 15.2 g. of2-(p-bromobenzyl)-6-isobutyl-pyridine with a small amount of toluene wasmixed therewith; after 30 minutes the above described solution ofdiethylaminoethylchloride was added, and after 2 hours 100 ccm. oftoluene was added thereto. The reaction mixture was stirred overnight atroom temperature. After the addition of water, the mixture wasseparated. The toluene solution was shaken up with an excess ofhydrochloric acid; and after the addition of caustic soda solution,shaken up with diethyl ether.

6 Upon distillation at 0.01 Torr, the residue of the ethereal portionyielded at 158-162 C. the 1-(6'-isobutylpyridyl- 2) 1 (p'bromophenyl)-3-diethylamino-propane. The picrate thereof, crystallizedfrom ethyl acetate, has a melting point of 149-151" C.

Example 8 142 g. of crudea-(B'-dimethylaminoethyl)-a-(6-isobutylpyridyl-2)-p-chlorobenzyl-cyanide[obtained by the condensation of a (,8dimethylaminoethynp-chlorobenzyl-cyanide with6-isobutyl-2-chloropyridine] was boiled in 700 g. of 75 percent sulfuricacid for 6 hours while stirring. Upon cooling, the mass was poured onice, extracted with diethyl ether, alkalinized with sodium hydroxide andextracted with diethyl ether. The residue, 102 g., obtained from thedried ethereal solution, was distilled at 0.01 Torr at 148-150 C. Therewas obtained 68.5 g. of 1-(p-chlorophenyl)-1-(6'-isobutylpyridyl2')-3-dimethylamino-propane.

Example 9 A mixture of 6.2 g. of1-(6-isobutyl-pyridyl-2')-1-(pbromophenyl)-3-amino-propane [obtained bythe condensation of 2-(p-bromobenzyl)-6-isobutyl-pyridine with ,8-aminoethyl-chloride], 5'0 ccm. cyclohexane and 1 g. acetone was allowedto stand for 24 hours at room temperature, was dried with potassiumcarbonate and hydrogenated with previously reduced platinum oxide incyclohexane. After 400 ccm. of hydrogen had been taken up, the reactionwas interrupted. The reaction mass was filtered to remove the catalystand the solvent evaporated off. From 6.6 g. of the residue there wasobtained on distillation at 0.01 Torr at -167 C. 4.7 g. ofl-(p-bromophenyl)-1-6'-isobutylpyridyl 2')-3-isopropyl-amino-propane.The picrate thereof has a melting point of 84- 89 C.

Example 10 16 g. of crude I-(p-bromophenyl)-1-(6'-isobutylpyn'dyl-Z-B-n-butylamino-propane-p-toluene sulfonamide [obtained by thecondensation of 2-(p-bromobenzyl)- 6-isobutyl-pyridine withN-(n-butyl)-N-(;8-ch10roethyl)- p-toluene-sulfonamide] in {100 g. of 70percent sulfuric acid was boiled under reflux for 6 hours. The reactionmixture was poured on ice and extracted with diethyl ether, alkalinizedwith caustic soda and extracted with diethyl ether. The residue obtainedfrom the ethereal extract, amounting to 10.5 g., yielded on distillationat 0.01 Torr at -176 C., 7.0 g. of 1-(p-bromophenyl)- 1-6'-isobutylpyridyl-2' 3 -n-butylamino-propane.

Example 11 4.2 g. of u-(p-bromophenyl)-a-(6-isobutylpyridyl-2)-propionacetal [obtained by the condensation of 2-(pbromobenzyl) 6isobutyl pyridine and bromoacetal, BrCH GH(OC H 5.6 ccm. ofdimethylformamide, 0.33 ccm. of hydrochloric acid (specific gravity1.19), and 0.85 ccm. of 85 percent formic acid were mixed and heated ina bath having a temperature of 180 C., using a descending cooler, untilthe inner temperature reached 155 C. without any further distillationtaking place. Then the mass was heated under reflux for 20 hours at abath temperature of 180 C. The dimethylformamide was distilled off in avacuum, the residue taken up in diethyl ether and the ethereal solutionshaken up with 2 N hydrochloric acid. The hydrochloric acid wasalkalinized with caustic soda, the precipitated base taken up in diethylether and the ethereal solution dried. There was obtained from theethereal solution a residue of 2.3 g. ofl-(p-bromophenyl)-l-(6-isobutyl-pyridyl-2)-3-dimethylaminopropane.

Example 12 2.5 g. of l-(p-bromophenyl)-1-(6'-isobutylpyridyl-2)-3-isopropyl-amino-propane, 0.83 g. of 90 percent 7 formic acid and0.60 g. of 35 percent formaldehyde were mixed while cooling; the mixtureheated on a steam bath until the principal evolution of CO ceased andthen for 12 hours at a bath temperature of 100 C. Upon the addition ofcc. of 2 N hydrochloric acid, the formaldehyde was distilled off undervacuum and the residue, obtained upon the addition of caustic soda, wasextracted with diethyl ether. The residue of the ethereal solution, 2.3g., yields with picric acid, the picrate of 1 (p bromophenyl) 1 (6isobutylpyridyl 2) 3- methyl-isopropylaminopropane, having a meltingpoint of ISO-156 C.

Example 13 A mixture of 15.0 g. of a-(p-chlorophenyl)-a-(6-isobutylpyridyl-2)-propionitrile, 4.0 g. of dimethylamine, 35 g. ofcyclohexane and 8.0 g. of Raney-nickel is hydrogenated under a hydrogenpressure of 160 atmospheres at room temperature. Upon completion of thehydrogenation, the mass is shaken up with water and the catalyst removedby filtration. The filtrate is dried and concentrated by evaporation.The obtained residue is distilled at 0.01 Torr at l46l49 C., yielding 11g. of 1 (p chlorophenyl) 1 (6 isobutylpyridyl 2')-3-dimethylaminopropane. The picrate thereof has a melting point of185l87 C.

Example 14 3.7 g. of omega-p-chlorophenyl-omega-(6-isobutyl'pyridyl-2)-propionic acid-diethylamide [obtained by the condensation of2-p-chlorobenzyl-6-isobutylpyridine with chloroaceticaeid-diethylarnide] in 250 ccm. of dry diethyl ether was reacted with0.76 g. of lithium aluminum hydride and boiled for 8 hours whilestirring. Then the excess lithium aluminum hydride was decomposed withmoist diethyl ether; the ethereal solution shaken up with water, dried,filtered, and concentrated by evaporation. Distillation of the residueat 0.01 Torr, at 155-158 C.,

yielded the 1-p-chlorophenyl 1-(6'-isobutylpyridyl-2')-3rdiethylamino-propane. The picrate thereof melts at l57-160 C.

It will be understood that the foregoing description of the inventionand the examples set forth are merely illustrative of the principlesthereof. Accordingly, the appended claims are to be construed asdefining the invention within the full spirit and scope thereof.

I claim:

1. A member of the group consisting of l-(6-isobutylpyridyl 2) 1 (pbromophenyl) 3 mono lower alkyl aminopropane, 1 (6' isobutylpyridyl 2')l- (p-chlorophenyl)-3-mono-lower alkyl amino propane, 1 (6'isobutylpyridyl 2) 1 (p bromophenyl)- 3-di-lower alkyl amino propane,and 1-(6'-isobutylpyridyl-2)-l-(p-chlorophenyl)-3-di-lower alkyl aminopropane, the carbon content of the lower alkyl radicals in the B-aminogroup totalling from 1 to 4 carbon atoms.

2. 1 (6' isobutylpyridyl 2) l (p bromophen' yl)-3-mono-methyl aminopropane.

3. 1 (6 isobutylpyridyl 2') 1 (p chlorophenyl)-3-mono-methyl aminopropane.

4. 1 (6 isobutylpyridyl 2) 1 (p chlorophenyl)-3-di-ethyl amino propane.

5. 1 (6' isobutylpyridyl 2) 1 (p -'chloro' phenyl)-3-di-ethylarninopropane.

6. 1 (6' isobutylpyridyl 2) l (p bromo phenyl)-3-diethylamino propane.

1 (6 isobutylpyridyl 2) l (p bromo' phenyl) -3-dimethylamino propane.

References Cited in the file of this patent UNITED STATES PATENTS2,567,245 Sperber et al. Sept. 11, 1951 2,585,239 Granatek Feb. 12, 19522,656,358 Sperber et al. Oct. 20, 1953 2,774,768 Ehrhart et al. Dec. 18,1956

1. A MEMBER OF THE GROUP CONSISTING OF 1-(6''-ISOBUTYLPYRIDYL -2'') -1 - (P - BROMOPHENYL) - 3 - MONO - LOWER ALKYL AMINOPROPANE, 1 - (6'' -ISOBUTYLPYRIDYL - 2'') - 1(P-CHLOROPHENYL)-3-MONO-LOWER ALKYL AMINOPROPANE, 1 - (6'' - ISOBUTYLPYRIDYL - 2'') - 1 - (P -BROMOPHENYL)3-DI-LOWER ALKYL AMINO PROPANE, AND1-(6''-ISOBUTYLPYRIDY1-2'')-1-(P-CHLOROPHENYL)-3-DI-LOWER ALKYL AMINOPROPANE, THE CARBON CONTENT OF THE LOWER ALKYL RADICALS IN THE 3-AMINOGROUP TOTALLING FROM 1 TO 4 CARBON ATOMS.